Synthesis of an S-Linked α(2→8) GD3 Antigen and Evaluation of the Immunogenicity of Its Glycoconjugate.

Replacing the interglycosidic oxygen atom of oligosaccharides with a nonhydrolyzable sulfur atom has attracted significant interest because it provides opportunities for developing new glycoconjugate vaccines. Herein, a stereocontrolled and highly convergent method to synthesize a non-reducing-end inter-S-glycosidic variant of the GD3 antigen (S-linked α(2→8) GD3) that is resistant to enzymatic hydrolysis is reported. The key steps in the synthesis are a regio- and stereoselective α(2→3) sialylation of a lactoside acceptor with a C8-iodide-derivatized sialyl donor and an anomeric S-alkylation, which enable stereoselective construction of a terminal S-linked α(2→8) disialyl residue. The sulfhydryl-reactive maleimide group was used as the linker for the well-defined conjugation of these antigens to the immunogenic protein keyhole limpet hemocyanin (KLH). Groups of mice were immunized with the GD3-KLH and S-linked GD3-KLH glycoconjugates in the presence of complete Freund's adjuvant. Microarray analysis of the sera showed the promise of the S-linked GD3-KLH vaccine: it stimulated a high immunoglobulin G response against S-linked GD3 and cross-reactivity with the O-linked GD3 antigen was low. The activity of the S-linked GD3-KLH vaccine was comparable to that of the O-linked GD3-KLH vaccine, which highlighted the effectiveness of generating glycoconjugate vaccines and immunotherapies by relatively simple means.

Stereoselective synthesis of S-linked α(2→8) and α(2→8)/α(2→9) hexasialic acids.

A new approach for the synthesis of S-linked α(2→8) and alternating α(2→8)/α(2→9) oligosialic acids by S-alkylation has been developed, using chemo- and stereoselective alkylation of a C2-thiolated sialoside donor (nucleophile) with either a C8- or C9-iodide-activated sialoside acceptor (electrophile). An efficient intramolecular acetyl group migration from the C7 to C9-position of the sialoside under mild basic conditions was used to generate the C8-iodide, the key sialyl acceptor (electrophile). Using this strategy, the syntheses of S-linked α(2→8) and α(2→8)/α(2→9) hexasialic acids were achieved.

Exploring the self-assembly of glycopeptides using a diphenylalanine scaffold.

Diphenylalanine, a key building block for organic nanotechnology, forms discrete, rigid and hollow nanotubes that are assembled spontaneously upon their dilution from organic phase into aqueous solution. Here we report the efficient preparation of several S-linked glycosylated diphenylalanine analogues bearing different monosaccharide, di-saccharide and sialic acid residues. The self-assembly studies revealed that these glycopeptides adopted various structures and glycosylation could be a tool to manipulate the self-assembly process. Moreover, the solubility of these analogues was found to be much greater than diphenylalanine, which could open new applications based on these nanostructures.

Asymmetric synthesis of bis-tetrahydrofuran cores in annonaceous acetogenins.

The bis-THF cores of annonaceous acetogenins were synthesized using (3R,4R)-1,5-hexadiene-3,4-diol (1) as the sole source of carbon atoms. The methylene acetal function was applied as a new linker/tether to facilitate the ring-closing metathesis.

1,2,3-Triazole derivatives as new cannabinoid CB1 receptor antagonists.

This letter reports the new entry of novel 1,2,3-triazole derivatives as CB1 receptor antagonists. The design, synthesis and biological evaluation of N1 and N2 substituted 1,2,3-trizoles are described. The N2 substituted, symmetrical 1,2,3-triazoles are more potent ligands than the unsymmetrical analogues. The in vitro activity of these triazoles is further improved by inserting a methylene group between the central core and the carbonyl side chain. The most potent antagonists prepared in this series (IC(50)<20 nM) are the triazoles containing benzyl amides. These triazoles also show excellent selectivity between CB1 and CB2 receptors (IC(50)>10 microM for CB2; CB2/CB1>1000).